Streptococcal pneumoniae (S. pneumoniae) is the most common pathogenic cause of bacterial pneumonia, and is also one of the major causes of bacterial otitis media (middle ear infections), meningitis and bacteremia. There are at least 83 types of the pneumococcal organism, each with a different chemical structure of the capsular polysaccharide. The capsular polysaccharide is the principal virulence factor of the pneumococcus and induces an antibody response in adults. Currently, a 23-polyvalent polysaccharide vaccine (such as Pnu-Imune.RTM., American Cyanamid Company, Wayne, N.J.) is available for adults and children over two years of age. Preparation of this purified pneumococcal polysaccharide vaccine is disclosed in U.S. Pat. Nos. 4,242,501, 4,221,906 and 4,686,102 (Bibliography entries 1,2,3). However, children less than two years of age do not induce a good immune response to this type of vaccine.
To modify the immunological characteristics and enhance the immunogenicity of the polysaccharide in children younger than two years of age, the polysaccharide has been covalently conjugated to a protein carrier to form a polysaccharide-protein conjugate. Preparation of the conjugate polysaccharide-protein conjugate vaccine is disclosed in U.S. Pat. No. 4,673,574 (4). The patent relates to the preparation of immunogenic conjugates comprising a polysaccharide fragment derived from the capsular polymer of S. pneumoniae or Haemophilus influenzae type b containing a reducing group(s) and a bacterial toxin or toxoid, specifically nontoxic diphtheria toxin (such as CRM.sub.197) as a protein carrier.
An effort to enhance the immunogenicity of a polysaccharide has been reported in which site-directed mutagenesis was used to generate non-toxic toxoids of a toxic S. pneumoniae protein, pneumolysin. The resulting mutant pneumolysin toxoids were conjugated to a Type 19F pneumococcal capsular polysaccharide through the use of linker or spacer, 6-aminocaproic acid. The conjugate enhanced the immunogenicity of the Type 19F polysaccharide moiety compared with that of the unconjugated polysaccharide (5,6). A follow-up study indicated that untoxoided native pneumolysin is unsuitable for inclusion in a vaccine because of its toxicity (7).
However, despite these and other efforts, there is no efficacious vaccine against S. pneumoniae for children less than two years of age. Thus, there is a need for such a vaccine.